© 2007 The Royal College of Psychiatrists
REAPPRAISAL |
Management of insomnia: treatments and mechanisms
Psychopharmacology Unit, University of Bristol, Bristol, UK
Correspondence: Dr David Nutt, Psychopharmacology Unit, University of Bristol, Dorothy Hodgkin Building, Whitson Street, Bristol BS1 3NY, UK. Email: david.j.nutt{at}bristol.ac.uk
Declaration of interest S.W. and D.N. have received funding from several pharmaceutical companies with an interest in the drug treatment of sleep disorder.
ABSTRACT
Management of insomnia is an interesting subject at present. New drug treatments are now becoming available after a relatively static period since the development of the Z-drugs in the 1990s. Moreover, more evidence is coming to light about the length of drug treatment and the effectiveness of psychological therapies. This article briefly describes current treatments, both evidence-based and common practice, and goes on to describe some emerging approaches.
Insomnia is the subjective experience of poor or unrefreshing sleep, usually with some objective evidence of reduced time asleep or delayed sleep onset, although often the subjective experience of suffering may appear more than expected from the degree of sleep shortening. If this occurs in the absence of psychiatric disorder, it is called primary insomnia. Insomnia in other psychiatric disorders is called secondary insomnia and is very common in depression, with up to 90% of patients with sleep disturbance. Sleep abnormalities predict poor response to cognitive–behavioural therapy (CBT) (Thase et al, 1995) and often continue to disrupt life even when mood has improved, contributing to the risk of relapse. In mania, insomnia often precedes a relapse and may be a useful warning sign of imminent mood swings. The loss of sleep may accelerate the upward mood shift, just as sleep deprivation can elevate mood in people with depression. Insomnia might offer an important signal of impending illness and an opportunity for prophylactic interventions.
DRUG TREATMENT
When measures to improve sleep habits have failed (see Morin & Espie, 2003), insomnia is usually treated with a variety of drugs – either those that increase brain inhibition through the GABA–A benzodiazepine receptor system or those that decrease excitation through blocking 5-hydroxytryptamine (5-HT) or histamine H1 receptors.
GABA-A receptor drugs
Benzodiazepines and the Z-drugs (zolpidem and zopiclone, and to a lesser
extent zaleplon) are the most commonly used hypnotics which act on the
benzodiazepine receptor, with the less selective agents clomethiazole and
choral hydrate having poor safety profiles. The Z-drugs have a better
pharmacokinetic profile than the older benzodiazepines
(Nutt, 2005), but are equally
efficacious (Dundar et al,
2004;
http://www.nice.org.uk/TA077)
and are the drugs of choice to avoid daytime carry-over effects. Doses are
usually halved in older adults (see British National Formulary;
http://www.bnf.org)
but elderly patients do tend to get up in the night and even short-acting
GABA-ergic drugs can compromise balance and cognition early in the night
(Allain et al, 2005).
The length of time that hypnotics show efficacy is less clear. In clinical
practice many patients are treated with hypnotics for many months or longer.
In a placebo-controlled trial of the active (S) enantiomer of zopiclone
(eszopiclone) efficacy was maintained over 6 months
(Krystal et al, 2003)
and there are now open-label continuation data for 12 months
(Roth et al, 2005).
These long-term controlled data showing continued efficacy of a hypnotic will
be reassuring to patients and their treating doctors. Nevertheless, withdrawal
reactions with rebound insomnia are still seen in some patients, even with the
newer agents, although the timing of these varies with the half-life of the
drug. Thus rebound insomnia would be expected on the first drug-free night
with drugs with short half-lives or several nights later with drugs with long
half-lives.
Antidepressants
Tricyclic and some other classes of antidepressants as well as
antipsychotics have long been used for the treatment of insomnia, whereas
selective serotonin reuptake inhibitors (SSRIs) generally disrupt sleep early
in a course of treatment. This effect of SSRIs on alertness can be offset by
sedative antidepressants such as trazodone, probably because they block
5-HT2 receptors which are being overstimulated by an increase in
5-HT (Kaynak et al,
2004). Other 5-HT2 antagonist antidepressants such as
nefazodone (Hicks et al,
2002) and mirtazapine (Winokur
et al, 2003) have been shown to reduce insomnia in
depression, especially early in treatment. There are no controlled studies of
the hypnotic efficacy of low-dose amitriptyline but despite this it is fairly
common in primary care practice to use 10 or 25 mg amitriptyline to promote
sleep. At this dose amitriptyline is probably acting mostly as a histamine
H1 receptor antagonist, although a degree of 5-HT2 and
cholinergic muscarinic antagonism may also contribute.
Antihistamines
Antihistamines have sedative effects and are sold over the counter as
sleeping medications. There is limited evidence that over-the-counter
antihistamines work, although recently some benefits have been reported for
diphenhydramine in mild insomnia. More profound effects on sleep have been
reported for both promethazine and hydroxyzine, although neither is available
over the counter and they have quite long half-lives so are likely to cause
hangover.
Antipsychotics
For decades sedative antipsychotics, especially thioridazine and
chlorpromazine, were used to treat more serious insomnia. More recently, as
the cardiac safety of these drugs – especially thioridazine – has
been questioned, atypical antipsychotics have been used in this role (most
usually olanzapine and quetiapine). These act by blocking 5-HT2 and
H1 receptors as well as muscarinic and
1-adrenoceptors, all of which contribute to sedation, but
there is no published controlled trial of atypical antipsychotics in
insomnia.
Melatonin receptor drugs
Melatonin is a hormone that helps to regulate circadian rhythms. There is a
strong public perception of melatonin as a sleep-promoting agent, which leads
many people to self-treat with supplies obtained over the internet or from
other countries. However, despite its obvious appeal, clinical efficacy data
in primary insomnia are very slight (see
Buscemi et al, 2005),
although there is some evidence of efficacy in disorders such as jet lag and
delayed sleep phase syndrome. Melatonin is also prescribed quite often by
child psychiatrists because it seems to have good tolerability, but its
efficacy has not been proven in large controlled studies
(Buscemi et al, 2006).
One such study is being conducted at present by the National Health Service
Technology Assessment Programme. In 2005, a synthetic analogue of melatonin,
ramelteon, was granted a licence for the treatment of insomnia in the USA.
Ramelteon acts in the same way as the natural hormone to stimulate melatonin
receptors and has been shown to promote the onset of sleep in
placebo-controlled trials (Erman et
al, 2006).
PSYCHOLOGICAL THERAPY FOR INSOMNIA
Psychological therapies for insomnia have been shown to be effective (Morin et al, 2006; Espie et al, 2007). Once a person experiences insomnia, worry about sleep itself often perpetuates the problem. Currently used psychotherapy for insomnia is a combination of behavioural and cognitive strategies which are given to individuals (Jacobs et al, 2004) or to groups (Jansson & Linton, 2005). The behavioural approaches reinforce natural sleep-initiating and maintaining processes, such as sticking to routines, minimising time in bed spent awake (so limiting rumination) and lowering physical and psychological arousal at bedtime. Cognitive therapy is based on knowledge of the presence of pre-sleep cognitions in patients who find it difficult to get to sleep. The CBT challenges these thoughts to bring about cognitive restructuring.
Cognitive–behavioural therapy for the treatment of insomnia has been evaluated in a number of studies with varying results, probably because of differences in patient groups and the nature, duration and setting of the treatment. Most reports reveal some improvements, which although modest in terms of sleep onset time and total sleeping time, are often greater in areas such as increased quality of life and decreased anxiety about sleep (Green et al, 2005).
A number of practical issues need to be considered when organising and evaluating these treatments, including selection of participants, access during working hours (many people with insomnia still work) and willingness to engage in the group. Therapists trained in CBT are rarely available as they are usually fully committed to patients with severe mental illness. However, CBT is effective and if available locally should be used for chronic insomnia. It is important to note that a person need not be off medication for the treatment to work.
CONCLUSIONS
Insomnia is common, especially in people with psychiatric disorder. It is often persistent and disabling and contributes to poorer treatment outcomes and lower quality of life. A summary of treatments for insomnia with their mechanisms of action is given in Table 1.
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Table 1 Efficacy and mechanisms in the treatment of insomnia
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Current hypnotics that act as agonists of the GABA–A benzodiazepine receptor system, especially the Z-drugs, are safe and effective and new data with eszopiclone shows efficacy for 6 months. However, some people do have trouble in stopping these drugs, owing in part to rebound. Antidepressants with 5-HT2 and H1 receptor-blocking properties are useful for promoting sleep, but tricyclic antidepressants are considerably less safe in overdose so should be used with caution. Antipsychotics have a role in severe insomnia associated with other psychiatric disorders, especially depression and psychosis.
Melatonin has some utility in sleep phase disorders (e.g. jet lag). The new synthetic analogue of melatonin, ramelteon, is effective in sleep-onset insomnia. Psychotherapeutic approaches, especially CBT, can be effective for primary insomnia and can work well in group settings.
REFERENCES
- Allain, H., tue-Ferrer, D., Polard, E., et al (2005) Postural instability and consequent falls and hip fractures associated with use of hypnotics in the elderly: a comparative review. Drugs and Aging, 22, 749 -765.[CrossRef][Medline]
- Buscemi, N., Vandermeer, B., Hooton, N., et al (2005) The efficacy and safety of exogenous melatonin for primary sleep disorders. A meta-analysis. Journal of General Internal Medicine, 20, 1151 -1158.[CrossRef][Medline]
- Buscemi, N., Vandermeer, B., Hooton, N., et al
(2006) Efficacy and safety of exogenous melatonin for
secondary sleep disorders and sleep disorders accompanying sleep restriction:
meta-analysis. BMJ, 332, 385
-393.
[Abstract/Free Full Text] - Dundar, Y., Dodd, S., Strobl, J., et al (2004) Comparative efficacy of newer hypnotic drugs for the short-term management of insomnia: a systematic review and meta-analysis. Human Psychopharmacology, 19, 305 -322.[CrossRef][Medline]
- Erman, M., Seiden, D., Zammit, G., et al (2006) An efficacy, safety, and dose-response study of Ramelteon in patients with chronic primary insomnia. Sleep Medicine, 7, 17 -24.[CrossRef][Medline]
- Espie, C. A., MacMahon, K. M., Kelly, H. L., et al (2007) Randomized clinical effectiveness trial of nurse-administered small-group cognitive behavior therapy for persistent insomnia in general practice. Sleep, 30, 574 -584.[Medline]
- Green, A., Hicks, J. A., Weeks, R., et al (2005) A cognitive-behavioural group intervention for people with chronic insomnia: an initial evaluation. British Journal of Occupational Therapy, 68, 518 -522.
- Hicks, J. A., Argyropoulos, S. V., Rich, A. S., et al
(2002) Randomised controlled study of sleep after nefazodone
or paroxetine treatment in out-patients with depression. British
Journal of Psychiatry, 180, 528
-535.
[Abstract/Free Full Text] - Jacobs, G. D., Pace-Schott, E. F., Stickgold, R., et al
(2004) Cognitive behavior therapy and pharmacotherapy for
insomnia: a randomized controlled trial and direct comparison.
Archives of Internal Medicine,
164, 1888
-1896.
[Abstract/Free Full Text] - Jansson, M. & Linton, S. J. (2005) Cognitive-behavioral group therapy as an early intervention for insomnia: a randomized controlled trial. Journal of Occupational Rehabilitation, 15, 177 -190.[CrossRef][Medline]
- Kaynak, H., Kaynak, D., Gozukirmizi, E., et al (2004) The effects of trazodone on sleep in patients treated with stimulant antidepressants. Sleep Medicine, 5, 15-20.[CrossRef][Medline]
- Krystal, A. D., Walsh, J. K., Laska, E., et al (2003) Sustained efficacy of eszopiclone over 6 months of nightly treatment: results of a randomized, double-blind, placebo-controlled study in adults with chronic insomnia. Sleep, 26, 793 -799.[Medline]
- Morin, C. M. & Espie, C. A. (2003) Insomnia: A Clinician's Guide to Assessment and Treatment. Kluwer.
- Morin, C. M., Bootzin, R. R., Buysse, D. J., et al (2006) Psychological and behavioral treatment of insomnia: update of the recent evidence (1998-2004). Sleep, 29, 1398 -1414.[Medline]
- Nutt, D. J. (2005) NICE: The National Institute
of Clinical Excellence - or Eccentricity? Reflections on the Z-drugs as
hypnotics. Journal of Psychopharmacology,
19, 125
-127.
[Free Full Text] - Roth, T., Walsh, J. K., Krystal, A., et al (2005) An evaluation of the efficacy and safety of eszopiclone over 12 months in patients with chronic primary insomnia. Sleep Medicine, 6, 487 -495.[CrossRef][Medline]
- Thase, M. E., Kupfer, D. J., Buysse, D. J., et al (1995) Electroencephalographic sleep profiles in single-episode and recurrent unipolar forms of major depression. I. Comparison during acute depressive states. Biological Psychiatry, 38, 506 -515.[CrossRef][Medline]
- Winokur, A., DeMartinis, N. A., III, McNally, D. P., et al (2003) Comparative effects of mirtazapine and fluoxetine on sleep physiology measures in patients with major depression and insomnia. Journal of Clinical Psychiatry, 64, 1224 -1229.
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